Heart failure is a pathophysiological state in which the heart fails to pump blood at a rate commensurate with the requirements of the metabolizing tissues of the body. It is caused in most cases (about 95% of cases) by myocardial failure.
The contractile proteins of the heart lie within the muscle cells (myocytes), which constitute about 75% of the total volume of the myocardium. The two major contractile proteins are the thin actin filament and the thick myosin filament. Each myosin filament contains two heavy chains and four light chains. The bodies of the heavy chains are intertwined, and each heavy chain ends in a head. Each lobe of the bibbed myosin head has an ATP-binding pocket, which has in close proximity the myosin ATPase activitythat breaks down ATP to its products.
The velocity of cardiac muscle contraction is controlled by the degree of ATPase activity in the head regions of the myosin molecules. The major determinant of myosin ATPase activity and, therefore, of the speed of muscle contraction, is the relative amounts is of the two myosin heavy chain isomers, alpha and beta (α-MHC and β-MHC). The α-MHC isoform has approximately four times more enzymatic activity than the β-MHC isoform and, consequently, the velocity of cardiac muscle shortening is related to the relative percentages of each isoform. For example, adult rodent ventricular myocardium has approximately 80–90% α-MHC and only 10–20% β-MHC, which explains why its myosin ATPase activity is 3–4 times greater than bovine ventricular myocardium, which contains 80–90% β-MHC.
When ventricular myocardial hypertrophy or heart failure is created in rodent models, a change occurs in the expression of MHC isoforms, with α-MHC decreasing and β-MHC becoming the dominant isoform. These “isoform switches” then reduce the contractility of the hypertrophied rodent ventricle, ultimately leading to myocardial failure. This pattern of altered gene expression has been referred to as reversion to a “fetal” pattern because, during fetal and early neonatal development, β-MHC also dominates in rodent ventricular myocardium.
Although human atrial myocardium may undergo similar isoform switches with hypertrophy or failure, human ventricular myocardium, the basis for the majority of cases of heart failure (greater than 90% of cases), has not been thought to exhibit this pattern. This is because several studies which examined this issue in autopsy cases did not find biologically significant expression of the α-MHC isoform in putatively normal hearts. Since there was thought to be no significant expression of α-MHC in normal hearts, a downregulation in α-MHC was not thought to be a possible basis for myocardial failure in humans. There has been one report that the amount of α-MHC, although extremely small to begin with, is reduced in failing human myocardium. Bouvagnet et al., Basic Res. Cardiol., 84, 91–102(1989). There have also been conflicting reports about the presence and amounts of α-MHC and β-MHC messenger RNA (mRNA) in normal and failing human myocardium. Cf. Arai et al., Circ. Res., 72,463 (1993) with Lowes et al., J. Invest. Med., 43, 316A (1995). However, as of 1997, those skilled in the art still considered it unlikely that a shift in myosin isoforms occurred in human myocardial failure. See Colucci and Braunwald, in Heart Disease: A Textbook of Cardiovascular Medicine (Braunwald ed., 5th ed., 1997), Chapter 13 at page 406. Indeed, MHC gene expression is considered to be a classical example of species variation in the expression of genes, and data on MHC gene expression in human disease states cannot be extrapolated from animal studies.
It has been shown that myocardial function declines with age in animals. Cellular and molecular mechanisms that account for age-associated changes in myocardial performance have been studied largely in rodents. Among other changes, marked shifts in MHC occur in rodents, i.e., the β isoform becomes predominant in senescent rats (85% β versus 15% α). Steady-state mRNA levels for α-MHC and β-MHC parallel the age-associated change in the MHC proteins. The myosin ATPase activity declines with the decline in α-MHC content, and the altered cellular profile results in a contraction that exhibits a reduced velocity and a prolonged time course. No similar studies are known to have been made in humans and, as noted above, data on MHC gene expression from animal studies cannot be extrapolated to humans.
For a detailed discussion of heart failure, MHC gene expression, and age-associated changes in cardiac performance, see Heart Disease: A Textbook of Cardiovascular Medicine (Braunwald ed., 5th ed., 1997).